Inhibitors of 5-HT2A receptor

ABSTRACT

Compounds of Formula (I):  
                 
 
wherein R and R′ are described herein, as are processes for preparing the compounds, pharmaceutical compositions comprising the compounds, and use of the compounds and compositions in the prophylaxis or treatment of a 5-HT 2A  receptor-related disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. application Ser. No.10/933,921, filed Sep. 2, 2004; U.S. provisional application Ser. No.60/505,295, filed Sep. 23, 2003; and to Swedish Patent Application No.0302369.4, filed Sep. 3, 2003. The prior applications are incorporatedherein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for theirpreparation, as well as to the use of the compounds for the preparationof a medicament against 5-HT_(2A) receptor-related disorders.

BACKGROUND

Many disorders and conditions of the central nervous system areinfluenced by the adrenergic, the dopaminergic, and the serotonergicneurotransmitter systems. For example, serotonin (5-HT;5-hydroxytryptamine) has been implicated in a number of disorders andconditions which originate in the central nervous system.

The HT_(2A) receptor has been implicated as a therapeutic target for thetreatment or prevention of abnormalities of the serotonergic system,including psychotic disorders such as schizophrenia (A. Carlsson, N.Waters and M. L. Carlsson, Biol. Psychiatry, 46, 1388 (1999); G. J.Marek and G. K. Aghajanian, Biol. Psychiatry, 44,1118 (1998); E.Sibelle, Z. Sarnyai, D. Benjamin, J. Gal, H. Baker and M. Toth, Mol.Pharmacol., 52, 1056 (1997)). Abnormality of this system has also beenimplicated in a number of human diseases such as mental depression(Arias B, Gutierrez B, Pintor L, Gasto C, Fananas L, Mol. Psychiatry(2001) 6, 239-242), migraine, epilepsy and obsessive-compulsive disorder(Luisa de Angelis, Current Opinion in Investigational Drugs (2002) 3 (1)106-112). 5-HT_(2A) antagonists may also be useful in the treatment ofsleep disorders such as insomnia and obstructive sleep apnea, anorexianervosa (Zlegler A, Gorg T, Lancet (1999) 353, 929), cardiovascularconditions such as hypertension, vasospasm, angina, Raynaud's phenomenonand thrombotic illness including stroke, glaucoma (T. Mano et al. and H.Takaneka et al., Investigative Ophthalmology and Visual Science, 1995,vol. 36, pages 719 and 734, respectively) and in the inhibition ofplatelet aggregation. Evidence also implies that selective 5-HT_(2A)receptor antagonists may also be useful in the treatment of alcohol andcocaine dependence (Maurel S, De Vry J, De Beun R, Schreiber, Pharmacol.Biochem Behav (1999) 89-96; McMahan L R, Cunningham K A, Pharmacol ExpTher (2001) 297, 357-363).

SUMMARY

One object of the present invention is a compound of the Formula (I)

wherein R is either

-   -   aryl optionally independently substituted with one or more of        C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, and halo-C₁₋₆-alkyl; or    -   aryl-C₁₋₆-alkyl optionally independently substituted with one or        more of C₁₋₆-alkoxy; or    -   C₃₋₈-cycloalkyl;    -   R′ is either    -   aryl optionally independently substituted with one or more of        halogen, C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, and cyano; or    -   aryloxy optionally independently substituted with one or more of        halogen and C₁₋₆-alkoxy; or    -   heteroaryl optionally independently substituted with one aryl        and/or one or more of halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy,        which aryl is optionally independently substituted with one or        more of halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy; and        pharmaceutically acceptable salts, hydrates, solvates,        geometrical isomers, tautomers, optical isomers, and prodrug        forms thereof.

It is preferred that R is selected from

-   -   phenyl independently substituted with one or more of methyl,        methoxy, ethoxy, fluoro, and trifluoromethyl;    -   benzyl independently substituted with one or more of methoxy;        and    -   cyclohexyl.

It is especially preferred that R is selected from 2-ethoxyphenyl,2,4-difluorophenyl, 3-(trifluoromethyl)phenyl, 3,4,5-trimethoxybenzyl,and cyclohexyl.

It is preferred that R′ is selected from

-   -   phenyl independently substituted with one or more of fluoro;    -   phenoxy independently substituted with one or more of methoxy;        and    -   indolyl independently substituted with one phenyl and/or one or        more of fluoro, chloro, methyl, and methoxy, which phenyl is        optionally independently substituted with one or more of fluoro,        chloro, methyl, and methoxy.

It is especially preferred that R′ is selected from 4-fluorophenyl,2,6-dimethoxyphenoxy, and 2-phenyl-3-indolyl.

Preferred compounds are given in Examples 1-5.

Another object of the present invention is a process for the preparationof a compound as mentioned above, which process comprises the step of

-   -   a) reacting an amine RNH₂    -   wherein R is either    -   aryl optionally independently substituted with one or more of        C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, and halo-C₁₋₆-alkyl; or    -   aryl-C₁₋₆-alkyl optionally independently substituted with one or        more of C₁₋₆-alkoxy; or    -   C₃₋₈-cycloalkyl;    -   with a cyanate, to give a compound of formula R—NH—CO—NH₂,    -   wherein R is as defined above,    -   b) alkylation of a compound of Formula (II)    -   wherein R″ is C₁₋₆-alkyl,    -   via displacement of a leaving group by reaction of the compound        of Formula (II) with an alkylating agent of the Formula        R′—CH₂—CH₂-LG,    -   wherein R′ is either    -   aryl optionally independently substituted with one or more of        halogen, C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, and cyano; or    -   aryloxy optionally independently substituted with one or more of        halogen and C₁₋₆-alkoxy; or    -   heteroaryl optionally independently substituted with one aryl        and/or one or more of halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy,        which aryl is optionally independently substituted with one or        more of halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy; and    -   LG is a leaving group,    -   to give a compound of Formula (III)        wherein R′ and R″ are as defined above,    -   c) reacting the products from steps a) and b) in the presence of        a base, such as sodium methoxide or potassium tert-butoxide, to        give a compound of Formula (I)        wherein R and R′ are as defined above.

Another object of the present invention is a compound as mentioned abovefor use in therapy, especially for use in the prophylaxis or treatmentof a 5-HT_(2A) receptor-related disorder.

Another object of the present invention is a pharmaceutical formulationcomprising a compound as mentioned above as active ingredient, incombination with a pharmaceutically acceptable diluent or carrier,especially for use in the prophylaxis or treatment of a 5-HT_(2A)receptor-related disorder.

Another object of the present invention is a method for treating a humanor animal subject suffering from a 5-HT_(2A) receptor-related disorder.The method can include administering to a subject (e.g., a human or ananimal, dog, cat, horse, cow) in need thereof an effective amount of oneor more compounds of any of the formulae herein, their salts, orcompositions containing the compounds or salts.

The methods delineated herein can also include the step of identifyingthat the subject is in need of treatment of the 5-HT_(2A)receptor-related disorder. Identifying a subject in need of suchtreatment can be in the judgment of a subject or a health careprofessional and can be subjective (e.g., opinion) or objective (e.g.,measurable by a test or diagnostic method).

Another object of the present invention is a method for the prophylaxisof a 5-HT_(2A) receptor-related disorder, which comprises administeringto a subject in need of such treatment an effective amount of a compoundas mentioned above.

Another object of the present invention is a method for modulating5-HT_(2A) receptor activity, which comprises administering to a subjectin need of such treatment an effective amount of a compound as mentionedabove.

Another object of the present invention is the use of a compound asmentioned above for the manufacture of a medicament for use in theprophylaxis or treatment of a 5-HT_(2A) receptor-related disorder.

The compounds as mentioned above may be agonists, partial agonists orantagonists for the 5-HT_(2A) receptor.

Examples of 5-HT_(2A) receptor-related disorders are schizophrenia,mental depression, migraine, epilepsy, obsessive-compulsive disorder,sleep disorders such as insomnia and obstructive sleep apnea, anorexianervosa, cardiovascular conditions such as hypertension, vasospasm,angina, Raynaud's phenomenon and thrombotic illness including stroke,glaucoma, alcohol and cocaine dependence.

The compounds and compositions are useful for treating diseases,including schizophrenia, mental depression, migraine, epilepsy,obsessive-compulsive disorder, sleep disorders such as insomnia andobstructive sleep apnea, anorexia nervosa, cardiovascular conditionssuch as hypertension, vasospasm, angina, Raynaud's phenomenon andthrombotic illness including stroke, glaucoma, alcohol and cocainedependence. In one aspect, the invention relates to a method fortreating or preventing an aforementioned disease comprisingadministrating to a subject in need of such treatment an effectiveamount of a compound or composition delineated herein.

Unless otherwise stated or indicated, the term “C₁₋₆-alkyl” denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said lower alkyl include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- andbranched-chain pentyl and hexyl. For parts of the range “C₁₋₆-alkyl” allsubgroups thereof are contemplated such as C₁₋₅-alkyl, C₁₋₄-alkyl,C₁₋₃-alkyl, C₁₋₂-alkyl, C₂₋₆-alkyl, C₂₋₅-alkyl, C₂₋₄-alkyl, C₂₋₃-alkyl,C₃₋₆-alkyl, C₄₋₅-alkyl, etc. “Halo-C₁₋₆-alkyl” means a C₁₋₆-alkyl groupsubstituted with one or more halogen atoms. Likewise, “aryl-C₁₋₆-alkyl”means a C₁₋₆-alkyl group substituted with one or more aryl groups.

Unless otherwise stated or indicated, the term “C₃₋₈-cycloalkyl” denotesa cyclic alkyl group having a ring size from 3 to 8 carbon atoms.Examples of said cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl.For parts of the range “C₃₋₈-cycloalkyl” all subgroups thereof arecontemplated such as C₃₋₇-cycloalkyl, C₃₋₆-cycloalkyl, C₃₋₅-cycloalkyl,C₃₋₄-cycloalkyl, C₄₋₈-cycloalkyl, C₄₋₇-cycloalkyl, C₄₋₆-cycloalkyl,C₄₋₅-cycloalkyl, C₅₋₇cylcoalkyl, C₆₋₇-cycloalkyl, etc.

Unless otherwise stated or indicated, the term “C₁₋₆ alkoxy” denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy. For parts of the range“C₁₋₆-alkoxy” all subgroups thereof are contemplated such asC₁₋₅-alkoxy, C₁₋₄-alkoxy, C₁₋₃-alkoxy, C₁₋₂-alkoxy, C₂₋₆-alkoxy,C₂₋₅-alkoxy, C₂₋₄-alkoxy, C₂₋₃-alkoxy, C₃₋₆-alkoxy, C₄₋₅-alkoxy, etc.

Unless otherwise stated or indicated, the term “halogen” shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term “aryl” refers to ahydrocarbon ring system having at least one aromatic ring. Examples ofaryls are phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl,naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl. The aryl ringsmay optionally be substituted with C₁₋₆-alkyl. Examples of substitutedaryl groups are 2-methylphenyl and 3-methylphenyl. Likewise, “aryloxy”refers to an aryl group bonded to an oxygen atom.

The term “heteroaryl” refers to a hydrocarbon ring system having atleast one aromatic ring having one or more ring atoms are a heteroatomsuch as O, N, or S, and the remaining ring atoms are carbon. Examples ofheteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl,quinazolinyl, indolyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl,dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothiazolyl,benzothiadiazolyl, and benzotriazolyl groups.

The term “leaving group” refers to a group to be displaced from amolecule during a nucleophilic displacement reaction. Examples ofleaving groups are iodide, bromide, chloride, methanesulfonate, hydroxy,methoxy, thiomethoxy, tosyl, or suitable protonated forms thereof (e.g.,H₂O, MeOH), especially bromide and methanesulfonate.

The term “alkylating agent” refers to a compound containing one or morealkyl groups which can be added to another compound. Examples ofalkylating agents include, but are not limited to, iodomethane,iodoethane, 1-iodopropane, 2-iodopropane, straight- andbranched-iodobutane, iodopentane, iodohexane, bromomethane, bomoethane,1-bromopropane, 2-bromopropane, straight- and branched-bromobutane,bromopentane, bromohexane, allyl bromide, ethyl methanesulfonate, methylmethanesulfonate, and propyl methanesulfonate.

“Pharmaceutically acceptable” means being useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes being useful forveterinary use as well as human pharmaceutical use.

“Treatment” as used herein includes prophylaxis of the named disorder orcondition, or amelioration or elimination of the disorder once it hasbeen established.

“An effective amount” refers to an amount of a compound that confers atherapeutic effect on the treated subject. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect).

The term “prodrug forms” means a pharmacologically acceptablederivative, such as an ester or an amide, which derivative isbiotransformed in the body to form the active drug. Reference is made toGoodman and Gilman's, The Pharmacological basis of Therapeutics, 8^(th)ed., Mc-Graw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p.13-15.

The following abbreviations have been used:

-   -   ACN means acetonitrile,    -   CHO means Chinese hamster ovary,    -   DEA means diethylamine,    -   DEPT means distortion enhancement polarisation transfer,    -   DMSO means dimethyl sulfoxide,    -   ELS means electron light scattering,    -   HPLC means high performance liquid chromatography,    -   Rt means retention time,    -   TFA means trifluoroacetic acid,    -   THF means tetrahydrofuran,    -   TLC means thin layer chromatography.

All isomeric forms possible (pure enantiomers, diastereomers, tautomers,racemic mixtures and unequal mixtures of two enantiomers) for thecompounds delineated are within the scope of the invention. Suchcompounds can also occur as cis- or trans-, E- or Z-double bond isomerforms. All isomeric forms are contemplated.

The compounds of the formula (I) may be used as such or, whereappropriate, as pharmacologically acceptable salts (acid or baseaddition salts) thereof. The pharmacologically acceptable addition saltsmentioned above are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms that the compounds are ableto form. Compounds that have basic properties can be converted to theirpharmaceutically acceptable acid addition salts by treating the baseform with an appropriate acid. Exemplary acids include inorganic acids,such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuricacid, phosphoric acid; and organic acids such as formic acid, aceticacid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid,glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonicacid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid,fumaric acid, succinic acid, malic acid, tartaric acid, citric acid,salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid,ascorbic acid and the like. Exemplary base addition salt forms are thesodium, potassium, calcium salts, and salts with pharmaceuticallyacceptable amines such as, for example, ammonia, alkylamines,benzathine, and amino acids, such as, e.g. arginine and lysine. The termaddition salt as used herein also comprises solvates which the compoundsand salts thereof are able to form, such as, for example, hydrates,alcoholates and the like.

For clinical use, the compounds of the invention are formulated intopharmaceutical formulations for oral, rectal, parenteral or other modeof administration. Pharmaceutical formulations are usually prepared bymixing the active substance, or a pharmaceutically acceptable saltthereof, with conventional pharmaceutical excipients. Examples ofexcipients are water, gelatin, gum arabicum, lactose, microcrystallinecellulose, starch, sodium starch glycolate, calcium hydrogen phosphate,magnesium stearate, talcum, colloidal silicon dioxide, and the like.Such formulations may also contain other pharmacologically activeagents, and conventional additives, such as stabilizers, wetting agents,emulsifiers, flavouring agents, buffers, and the like.

The formulations can be further prepared by known methods such asgranulation, compression, microencapsulation, spray coating, etc. Theformulations may be prepared by conventional methods in the dosage formof tablets, capsules, granules, powders, syrups, suspensions,suppositories or injections. Liquid formulations may be prepared bydissolving or suspending the active substance in water or other suitablevehicles. Tablets and granules may be coated in a conventional manner.

In a further aspect the invention relates to methods of making compoundsof any of the formulae herein comprising reacting any one or more of thecompounds of the formulae delineated herein, including any processesdelineated herein. The compounds of the formula (I) above may beprepared by, or in analogy with, conventional methods.

The processes described above may be carried out to give a compound ofthe invention in the form of a free base or as an acid addition salt. Apharmaceutically acceptable acid addition salt may be obtained bydissolving the free base in a suitable organic solvent and treating thesolution with an acid, in accordance with conventional procedures forpreparing acid addition salts from base compounds. Examples of additionsalt forming acids are mentioned above.

The compounds of formula (I) may possess one or more chiral carbonatoms, and they may therefore be obtained in the form of opticalisomers, e.g. as a pure enantiomer, or as a mixture of enantiomers(racemate) or as a mixture containing diastereomers. The separation ofmixtures of optical isomers to obtain pure enantiomers is well known inthe art and may, for example, be achieved by fractional crystallizationof salts with optically active (chiral) acids or by chromatographicseparation on chiral columns.

The chemicals used in the synthetic routes delineated herein mayinclude, for example, solvents, reagents, catalysts, and protectinggroup and deprotecting group reagents. The methods described above mayalso additionally include steps, either before or after the stepsdescribed specifically herein, to add or remove suitable protectinggroups in order to ultimately allow synthesis of the compounds. Inaddition, various synthetic steps may be performed in an alternatesequence or order to give the desired compounds. Synthetic chemistrytransformations and protecting group methodologies (protection anddeprotection) useful in synthesizing applicable compounds are known inthe art and include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994);and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons (1995) and subsequent editions thereof.

The necessary starting materials for preparing the compounds of formula(I) are either known or may be prepared in analogy with the preparationof known compounds. The dose level and frequency of dosage of thespecific compound will vary depending on a variety of factors includingthe potency of the specific compound employed, the metabolic stabilityand length of action of that compound, the patient's age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the condition to betreated, and the patient undergoing therapy. The daily dosage may, forexample, range from about 0.001 mg to about 100 mg per kilo of bodyweight, administered singly or multiply in doses, e.g. from about 0.01mg to about 25 mg each. Normally, such a dosage is given orally butparenteral administration may also be chosen.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DETAILED DESCRIPTION

In the examples below, all reagents were commercial grade and were usedas received without further purification, unless otherwise specified.Commercially available anhydrous solvents were used for reactionsconducted under inert atmosphere. Reagent grade solvents were used inall other cases, unless otherwise specified. Column chromatography wasperformed on Matrex® silica gel 60 (35-70 micron). TLC was carried outusing pre-coated silica gel F-254 plates (thickness 0.25 mm). ¹H NMRspectra were recorded on a Bruker Avance250 at 250 MHz. Chemical shiftsfor ¹H NMR spectra are given in part per million and eithertetramethylsilane (0.00 ppm) or residual solvent peaks were used asinternal reference. Splitting patterns are designated as follows: s,singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet;br, broad. Coupling constants are given in Hertz (Hz). Only selecteddata are reported. The ¹³C NMR spectra were recorded at 62.5 MHz. DEPTexperiments were used to help assign ¹³C NMR resonances where necessary.Chemical shifts for ¹³C NMR spectra are expressed in parts per millionand residual solvent peaks were used as internal reference. HPLCanalyses were performed using a Waters Xterra MS C18 column (100×4.6 mm,5 μ) eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5%water (0.2% TFA buffer) over 3.5 mins, then 95% ACN in 5% water (0.2%TFA buffer) for a further 2.5 mins at a flow rate of 3 ml/min on aWaters 600E or Gilson system with monitoring at 254 rn. Reverse phasepreparative HPLC was carried out using a Xterra MS C18 column (100×19mm, 5 μm) eluting with a gradient of 5% ACN in 95% water to 95% ACN in5% water (0.05% DEA) over 12.0 mins, then 95% ACN in 5% water (0.05%DEA) for a further 5.0 mins at a flow rate of 25 ml/min with monitoringat 254 nm. The fractions that contained the desired product wereconcentrated under reduced pressure and the resultant residue waslyophilised from a mixture of dioxane and water. Electrospray MS spectrawere obtained on a Micromass platform LCMS spectrometer. Compounds werenamed using AutoNom 2000.

EXAMPLE 11-[2-(2-phenyl-1H-indol-3-yl)ethyl]-N-{([(3,4,5-trimethoxybenzyl)amino]carbonyl}piperidine-4-carboxamide

Step 1: (3,4,5-Trimethoxy-benzyl)-urea

To a solution of 3,4,5-trimethoxybenzylamine (1.0496 g, 5.32 mmol) inwater (4 mL) were added conc. HCl (1 mL) and potassium cyanate (3.45 g,42.5 mmol) and the solution was stirred at 90° C. for 2 h. The mixturewas then cooled to room temperature and the solid was filtered andwashed with water to yield a white solid (1 g, 78.2%).

¹H-NMR(250MHz, DMSO-d₆) δ=3.60 (s, 3H, —OMe), 3.73 (s, 6H, —OMe), 4.08(d, 2H, J=6.0 Hz, —CH₂—Ar), 5.54 (s, 2H, —NH₂), 6.42 (t, 1H, J=6.0 Hz,—NH), 6.55 (s, 2H, Harom). HPLC 98%, Rt=1.30 min. MS (ES) m/z 241.24(M+H).

Step 2: Methanesulfonic acid 2-(2-phenyl-1H-indol-3-yl)-ethyl ester

Methane sulfonyl chloride (0.247 mL, 3.18 mmol) was added dropwise at 0°C. to a solution of 2-(2-phenyl-1H-indol-3-yl)-ethanol (606mg, 2.55mmol)and triethylamine (0.56 mL, 4 mmol) in dry dichloromethane (5 mL). After40 min the solution was poured into 1N HCl, the organic layer wasseparated, washed with water, brine, dried over magnesium sulfate andconcentrated under vacuum to afford a red oil (0.8 g, 100%).

¹H-NMR(250 MHz, CDCl₃) δ=2.79 (s, 3H, -Me), 3.37 (t, 2H, J=7.4 Hz,—CH₂—Ar), 4.48 (t, 2H, J=7.3 Hz,—CH₂—O—), 7.17-7.34 (m, 4H, Harom),7.39-7.67 (m, 5H, Harom), 8.20 (s, 1H, —NH). HPLC 94%, Rt=2.95 min. MS(AP) m/z no molecular ion found.

Step 3: 1-[2-(2-Phenyl-1H-indol-3yl)-ethyl]-piperidine-4-carboxylic acidmethyl ester

A solution of methanesulfonic acid 2-(2-phenyl-1H-indol-3-yl)-ethylester (0.8 g, 2.5 mmol), methyl isonipecotate (0.473 mL, 3.5 mmol) andsodium hydrogen carbonate (0.9 g, 11 mmol) in dry acetonitrile (5 mL)was stirred at 80° C. for 20 h. The solution was cooled, filtered andconcentrated under vacuum to afford a yellow oil (0.5 g) that could notbe purified by column chromatography due to decomposition on silica oron alumina. The intermediate was engaged in the next step (coupling withurea) without further purification.

Step 4:1-[2-(2-phenyl-1H-indol-3-yl)ethyl]-N-{[(3,4,5-trimethoxybenzyl)amino]carbonyl}piperidine-4-carboxamide

To a solution of 3,4,5-trimethoxybenzylurea (97.2 mg, 0.4 mmol),1-[2-(2-phenyl-1H-indol-3yl)-ethyl]-piperidine-4-carboxylic acid methylester (220 mg, 0.6 mmol) in dimethylacetamide (3 mL) was added sodiummethoxide (0.45 mL, 25% wt sol. in MeOH, 2.0 mmol). The reaction wascarried out on a rotary evaporator for 1 h to remove any trace ofmethanol. Water was then added and the compound extracted with ethylacetate. The compound was purified by preparative-hplc under basicconditions (DEA) to afford a white solid (29.3 mg, 13%).

¹H-NMR (250 MHz, CDCl₃) δ=1.77-1.90 (m, 4H, piperidine), 2.04 (dd, 2H,J=2.75/11.4 Hz, —CH₂—), 2.12-2.25 (m, 1H, —CH—CO), 2.66-2.72 (m, 2H,—CH₂—), 3.06-3.13 (m, 4H, 2-CH₂), 3.82 (s, 3H, —OMe), 3.85 (s, 6H,—OMe), 4.40 (d, 2H, J=5.8 Hz, —Ar), 6.53 (s, 2H, Harom), 7.11-7.25 (m,2H, Harom), 7.37-7.67 (m, 7H, Harom), 8.05 (d, 2H, J=7.8 Hz, —NH), 8.72(t, 1H, J=5.56Hz, —NH). HPLC 100%, Rt=3.59 min. MS (ES) m/z 571.02(M+H).

EXAMPLE 21-[2-(2,6-dimethoxyphenoxy)ethyl]-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)piperidine-4-carboxamide

To a solution of (3-trifluoromethyl-phenyl)-urea (synthesized using asimilar procedure to Example 1, Step 1) (0.1699 g, 0.83 mmol) and1-[2-(2,6-dimethoxy-phenoxy)-ethyl]-piperidine-4-carboxylic acid methylester (synthesized using a similar procedure to Example 1, Step 3)(0.2635 g, 0.81 mmol) in dimethylacetamide (2.0 mL) was added sodiummethoxide (0.9 mL, 25% in MeOH, 4.0 mmol). The reaction was stirred for1 h under vacuum on a rotary evaporator at room temperature. Water (10mL) was added, a white precipitate formed. The solid was filtered andwash with water. The solid was dissolved in ethyl acetate and thesolution washed with water. The organic layer was dried (MgSO₄) and thesolvent concentrated to about 0.5 mL. White crystals formed. Thecrystals were filtered and washed with a small amount of ethyl acetate.The product was obtained as white crystals (0.1157 g, 29%).

¹H-NMR (250 MHz, CDCl₃) δ=1.86-1.95 (m, 4H, CH₂), 2.05-2.19 (m, 2H,—CH₂—), 2.33-2.43 (m, 1H, —CH—CO), 2.80 (t, 2H, J=5.9Hz, —CH₂—),3.14-3.19 (m, 2H, —CH₂N), 3.83 (s, 6H, 2x-OMe), 4.10 (t, 2H, J=5.9 Hz,—CH₂O), 6.57 (d, 2H, J=8.4 Hz, Harom), 6.99 (t, 1H, J=8.4 Hz, Harom),7.34-7.47 (m, 2H, Harom), 7.60 (brd, 1H, J=8.0 Hz, Harom), 7.98 (s, 1H,Harom), 9.78 (s, 1H, —NH) and 10.92 (s, 1H, —NH). ¹³C-NMR (62.5 MHz,CDCl₃) δ=26.3, 41.9, 51.1, 54.1, 56.1, 68.5, 103.2, 115.0, 121.2, 121.7,127.6, 135.2, 135.8, 150.4, 151.7 and 175.9. HPLC 99%, Rt=2.25 min. MS(ES) m/z 496 (M+H).

EXAMPLE 3N-[(cyclohexylamino)carbonyl]-1-[2-(2-phenyl-1H-indol-3-yl)ethyl]piperidine-4-carboxamide

To a solution of cyclohexylurea (synthesized using a similar procedureto Example 1, Step 1) (75.1 mg, 0.5 mmol) and1-[2-(2-phenyl-1H-indol-3yl)-ethyl]-piperidine-4-carboxylic acid methylester (synthesized using a similar procedure to Example 1, Step 3)(253.3 mg, 0.75 mmol) in dimethylacetamide (5 mL) was added sodiummethoxide (0.7 mL, 25% wt in MeOH, 3.14 mmol). The reaction was carriedout on a rotary evaporator for 1 h to remove any trace of methanol.Water was then added and attempts to extract the compound with ethylacetate or chloroform failed. The aqueous layer was therefore evaporatedto dryness, acetonitrile was added, the solution dried over magnesiumsulfate and concentrated to give a yellow solid which was purified bypreparative-hplc under basic condition (DEA) and afford a white solid(5.8 mg, 3%). HPLC 100%, Rt=3.97 min. MS (ES) m/z 473.00 (M+H).

GENERAL PROCEDURE A FOR EXAMPLES 4 AND 5 (LIBRARY COMPOUNDS)

To a stirred solution of urea (synthesized using a similar procedure toExample 1, Step 1) (0.20 mmol) in DMSO (0.5 ml) was added potassiumtert-butoxide (0.40 mmol) as a DMSO solution and the reactions shaken atroom temperature. After 15 minutes a solution of the ester (synthesizedusing a similar procedure to Example 1, Step 3) (0.2 mmol) in DMSO wasadded and the contents shaken for a further 18 hours. The reactions weresubsequently filtered over amberlite™-IR-120(H) resin and purified bypreparative chromatography using the following conditions: Mobile phase.0.2% TFA/water, ACN Flow rate 25 ml/min. Gradient: 85/15 H₂0 + 0.2%TFA/ACN for 1.5 min.  5/95 in 9.5 min. for 1.5 min. 85/15 in 0.5 min.Detector: ELS. (approx. 1.5 ml/min flow split to Sedex 55 ELSD) Gas(Nitrogen) 2.0 bar Nebulizer 40° C. Column: Waters SymmetryPrep ™ 19 mm× 150 mm × 7 μm C18

EXAMPLE 4N-{[(2,4-difluorophenyl)amino]carbonyl}-1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxamide

Example 4 was synthesized according to General procedure A. HPLC 100%,Rt=3.88 min. MS (AP) m/z 406 (M+H).

EXAMPLE 5N-{[(2-ethoxyphenyl)amino]carbonyl}-1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxamide

Example 5 was synthesized according to General procedure A. HPLC 97%, Rt=3.96 min. MS (AP) m/z 414 (M+H).

EXAMPLE 6

Preparation of Tablets Ingredients mg/tablet 1. Active compound offormula (I) 10.0 Cellulose, microcrystalline 57.0 3. Calcium hydrogenphosphate 15.0 4. Sodium starch glycolate 5.0 5. Silicon dioxide,colloidal 0.25 6. Magnesium stearate 0.75

The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 forabout 10 minutes. The magnesium stearate is then added, and theresultant mixture is mixed for about 5 minutes and compressed intotablet form with or without fihn-coating.

Primary Screening and IC₅₀ Determination

CHO cells expressing 5-HT_(2A) receptors seeded in 384 well plates arepre-loaded with Fluo-4AM fluorescent dye and then incubated withcompound (10 μM for primary screen) for 15 min. Fluorescent intensity isrecorded using a Fluorometric imaging plate reader (FLIPR384, MolecularDevices) and inhibition of the peak response evoked by 5-HT (EC₇₀concentration) is calculated.

IC₅₀ determinations are performed utilizing the same functional assay asdescribed for primary screening (15 min antagonist compoundpre-incubation), applying the compounds in the dose range of 3 nM to 10μM.

In Vitro Receptor Pharmacology Selectivity Determinations

The affinity constants of compounds were determined using recombinanthuman serotonin receptors stably expressed in fibroblast cell lines (CHOor HEK293), measuring the ability of the compounds to displaceradio-labelled tracers using scintillation proximity assays or filterbinding assays. For 5-HT_(1B), 5-HT_(2B) and 5-HT_(2C) receptor bindingstudies ³H-LSD was used as radio ligand, for 5-HT_(2A) and 5-HT₆ ³H-5-HTwas used as tracer, while the binding constant to 5-HT_(1A) wasdetermined using ³H-8-OH-DPAT. The non-selective serotonin receptorantagonist mianserine was used as reference substance.

The activity at 5-HT_(2C) receptors was studied in a FLIPR based assay,measuring the effect of compounds on 10 nM 5-HT induced_Ca²⁺-currents.

The calculation of the K_(i) values for the inhibitors was performed byuse of Activity Base. The K_(i) value is calculated from IC₅₀ using theCheng Prushoff equation (with reversible inhibition that follows theMichaelis-Menten equation): K_(i)=IC₅₀ (1+[S]/K_(m)) [Cheng, Y. C.;Prushoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The compoundsof Formula (I) exhibit IC₅₀ values for the 5-HT_(2A) receptor in therange from 1 nM to 10 μM.

5-HT_(2A) antagonist lead compounds were identified in FLIPR-basedfunctional screening of the 5-HT_(2A) receptor. One of these compoundswere tested in equilibrium displacement binding measurements. Theresults show that Example 2 is a high affinity ligand for the 5-HT_(2A)receptor subtype, with a K_(i) value in the nanomolar range. Thecompound is highly selective over five other serotonin receptors assayed(5-HT_(2C), 5-HT_(2B), 5-HT_(1A), 5-HT₆ and 5-HT_(1B)). Example 2 isshown also to be selective at 5-HT_(2A) versus the 5-HT_(2C) receptor interms of efficacy. Functional K_(i)(nM) Binding K_(i)(nM) Example5-HT_(2A) 5-HT_(1A) 5-HT_(1B) 5-HT_(2A) 5-HT_(2B) 5-HT_(2C) 5-HT₆Example 2 32.3 >1000 >1000 23 >1000 >1000 >1000

The table shows the selectivity of Example 2 for the 5-HT_(2A) overother serotonin-binding receptors.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A compound of the Formula (I)

wherein R is selected from: aryl optionally independently substitutedwith one or more of C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, andhalo-C₁₋₆-alkyl; aryl-C₁₋₆-alkyl optionally independently substitutedwith one or more of C₁₋₆-alkoxy; and C₃₋₈-cycloalkyl; R′ is selectedfrom aryl optionally independently substituted with one or more ofhalogen, C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, and cyano; aryloxy optionallyindependently substituted with one or more of halogen and C₁₋₆-alkoxy;heteroaryl optionally independently substituted with one aryl and/or oneor more of halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy, which aryl isoptionally independently substituted with one or more of halogen,C₁₋₆-alkyl, and C₁₋₆-alkoxy; and pharmaceutically acceptable salts,hydrates, solvates, geometrical isomers, tautomers, optical isomers, andprodrug forms thereof:
 2. A compound according to claim 1, wherein R isselected from: phenyl independently substituted with one or more ofmethyl, methoxy, ethoxy, fluoro, and trifluoromethyl; benzylindependently substituted with one or more of methoxy; and cyclohexyl.3. A compound according to claim 1, wherein R is selected from2-ethoxyphenyl, 2,4-difluorophenyl, 3-(trifluoromethyl)phenyl,3,4,5-trimethoxybenzyl, and cyclohexyl.
 4. A compound according to claim1, wherein R′ is selected from: phenyl independently substituted withone or more of fluoro; phenoxy independently substituted with one ormore of methoxy; and indolyl independently substituted with one phenyland/or one or more of fluoro, chloro, methyl, and methoxy, which phenylis optionally independently substituted with one or more of fluoro,chloro, methyl, and methoxy.
 5. A compound according to claim 1, whereinR′ is selected from 4-fluorophenyl, 2,6-dimethoxyphenoxy, and2-phenyl-3-indolyl.
 6. A compound according to claim 1, which isselected from:1-[2-(2-phenyl-1H-indol-3-yl)ethyl]-N-{[(3,4,5-trimethoxybenzyl)amino]carbonyl}piperidine-4-carboxamide,1-[2-(2,6-dimethoxyphenoxy)ethyl]-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)piperidine-4-carboxamide,N-[(cyclohexylamino)carbonyl]-1-[2-(2-phenyl-1H-indol-3-yl)ethyl]piperidine-4-carboxamide,N-{[(2,4-difluorophenyl)amino]carbonyl}-1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxamide,andN-{[(2-ethoxyphenyl)amino]carbonyl}-1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxamide.7. A process for the preparation of a compound according to claim 1,which process comprises the steps of: a) reacting an amine RNH₂ whereinR is: aryl optionally independently substituted with one or more ofC₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, and halo-C₁₋₆-alkyl; aryl-C₁₋₆-alkyloptionally independently substituted with one or more of C₁₋₆-alkoxy;C₃₋₈-cycloalkyl; with a cyanate, to give a compound of formulaR—NH—CO—NH₂, wherein R is as defined above; b) alkylation of a compoundof Formula (II)

wherein R″ is C₁₋₆-alkyl, via displacement of a leaving group byreaction of the compound of Formula (II) with an alkylating agent of theFormula R′—CH₂—CH₂-LG, wherein R′ is: aryl optionally independentlysubstituted with one or more of halogen, C₁₋₆-alkoxy, halo-C₁₋₆-alkyl,and cyano; aryloxy optionally independently substituted with one or moreof halogen and C₁₋₆-alkoxy; heteroaryl optionally independentlysubstituted with one aryl and/or one or more of halogen, C₁₋₆-alkyl, andC₁₋₆-alkoxy, which aryl is optionally independently substituted with oneor more of halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy; and LG is a leavinggroup, to give a compound of Formula (III)

wherein R′ and R″ are as defined above, c) reacting the products fromsteps a) and b) in the presence of a base, such as sodium methoxide orpotassium tert-butoxide, to give a compound of Formula (I)

wherein R and R′ are as defined above.
 8. A pharmaceutical formulationcomprising a compound according to claim 1 as active ingredient, incombination with a pharmaceutically acceptable diluent or carrier.
 9. Amethod for the prophylaxis or treatment of a 5-HT_(2A) receptor-relateddisorder, which comprises administering to a subject in need of suchtreatment an effective amount of a compound according to claim
 1. 10.The method according to claim 9, wherein the disorder is selected fromschizophrenia, mental depression, migraine, epilepsy,obsessive-compulsive disorder, sleep disorders such as insomnia andobstructive sleep apnea, anorexia nervosa, cardiovascular conditionssuch as hypertension, vasospasm, angina, Raynaud's phenomenon andthrombotic illness including stroke, glaucoma, alcohol and cocainedependence.
 11. A method for modulating 5-HT_(2A) receptor activity,which comprises administering to a subject in need of such treatment aneffective amount of a compound according to claim 1.